Pyrimidothienoindazoles

ABSTRACT

The invention relates to novel pyrimidothienoindazoles of formula (I), processes for their preparation and their use for preparing medicaments for the treatment or prophylaxis of disorders, especially of hyperproliferative disorders.

This application claims benefit of U.S. Provisional Application Ser. No.60/622,640; filed on Oct. 27, 2004, the content of which is incorporatedherein by reference in its entirety.

This invention relates to novel pyrimidothienoindazoles, processes fortheir preparation and their use for preparing medicaments for thetreatment or prophylaxis of disorders, especially of hyperproliferativedisorders.

Epidermal growth factor receptors (EGFRs) comprise a family consistingof four known tyrosine kinase receptors, HER1 (EGFR, ErbB1), HER2 (neu,ErbB2), HER3 (ErbB3) and HER4 (ErbB4). These receptors are activated bya number of ligands including EGF, TGFα, epiregulin, amphiregulin andheregulins (neuregulins). The HER family receptors generate cellsignaling cascades that transduce extracellular stimulation intointracellular events that control various cellular functions includingproliferation, differentiation and apoptosis. These receptors areelevated in a large number of solid tumors and this increase has beenassociated with the disruption of normal cellular control resulting inmore aggressive tumors and a poor disease prognosis. Inhibitors ofepidermal growth factor receptors have resulted in stabilization orregression of tumor growth in a broad range of tumor types (Holbro, T.,Civenni, G., and Hynes, N. Exp Cell Res. 284: 99-110, 2003). It isbelieved that the compounds in this invention provide theiranti-proliferative effect through the inhibition of the tyrosine kinaseactivities of epidermal growth factor receptors (in particular ErbB1 andErbB2).

U.S. Pat. No. 5,679,683 (Pfizer) and WO 97/13760 (Glaxo Wellcome)describe tricyclic compounds capable of inhibiting tyrosine kinases ofthe epidermal growth factor receptor family.

U.S. Pat. No. 6,482,948 (Nippon Soda), U.S. Pat. No. 6,130,223, U.S.Pat. No. 6,495,557, WO 00/78767, WO 01/019369, WO 01/021620, US2003/153585, US 2003/022906, US 2004/058940, US 2004/077664 and WO02/072100 (Merck GmbH) disclose tricyclic compounds as PDE inhibitors.

WO 03/057149 (Bayer) describes heteropyrimidines andhetero-4-pyrimidones for the treatment of PDE7_(B)-mediated diseases.

The present invention relates to a compound of formula (I)

whereinR¹ is selected from the group consisting of hydrogen, methyl, ethyl, andhalo;R² is selected from the group consisting of hydrogen, methyl, ethyl, andhalo;R³ is selected from the group consisting of hydrogen, alkyl, halo,hydroxy, alkoxy, trifluoromethoxy, benzyloxy, halogenated benzyloxy,alkylated benzyloxy, pyridoxy, alkylated pyridoxy, halogenated pyridoxy,pyridylmethoxy, halogenated pyridylmethoxy, and N-morpholinyl, orR² and R³, together with the carbon atoms to which they are attached,form an pyrazole ring, wherein said pyrazole ring can optionally besubstituted with 0, 1 or 2 substituents independently selected from thegroup consisting of alkyl, benzyl, halogenated benzyl, pyridylmethoxy,and halogenated pyridylmethoxy;R⁴ is selected from the group consisting of hydrogen, alkyl, cyano, andhalo;R⁵ is selected from the group consisting of hydrogen, alkyl, and halo;R⁶ is selected from the group consisting of hydrogen, and alkyl;R⁷ is selected from the group consisting of hydrogen, and alkyl, orR⁷ is a heterocycle selected from the group consisting of pyrrolidinyl,morpholinyl, piperidinyl, and piperazinyl, orR⁷ is alkyl selected from the group consisting of methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl and t-butyl, wherein said alkyl issubstituted with 1, 2 or 3 independently selected substituents R⁷⁻¹,wherein R⁷⁻¹ is selected from the group consisting of halo, hydroxy,alkoxy, alkylsulfonyloxy, and amino, orR⁷⁻¹ is alkylamino, wherein said alkylamino can optionally besubstituted with 0, 1 or 2 substituents independently selected from thegroup consisting of hydroxy, alkoxy, amino, alkylamino, alkylsulfonyl,pyrrolidinyl, morpholinyl, piperidinyl, and piperazinyl, orR⁷⁻¹ is alkenylamino, wherein said alkenylamino can optionally besubstituted with 0, 1 or 2 substituents independently selected from thegroup consisting of oxo, hydroxy, alkoxy, amino, alkylamino,alkylsulfonyl, N-pyrrolidinyl, N-morpholinyl, N-piperidinyl, andN-piperazinyl, orR⁷⁻¹ is a heterocycle selected from the group consisting ofpyrrolidinyl, imidazolidinyl, imidazolyl, pyrazolyl, morpholinyl,piperidinyl, piperazinyl, and thiomorpholinyl, wherein said heterocyclecan optionally be substituted with 0, 1 or 2 substituents independentlyselected from the group consisting of alkyl, halo, hydroxy, alkoxy,amino, alkylamino, hydroxyalkyl, alkoxyalkyl, carboxyl, alkoxycarbonyl,N-pyrrolidinyl, N-piperidinyl, N-piperazinyl, pyrazinyl, benzyl, andpyridylmethyl, orR⁷ is alkenyl selected from the group consisting of allyl, prop-1-enyl,2-methyl-prop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, pent-2-enyl,pent-3-enyl, pent-4-enyl, wherein said alkenyl is substituted with 1, 2or 3 independently selected substituents R⁷⁻²,wherein R⁷⁻² is oxo, orwherein R⁷⁻² is alkylamino, wherein said alkylamino can optionally besubstituted with 0, 1 or 2 substituents independently selected from thegroup consisting of oxo, hydroxy, alkoxy, amino, and alkylamino;or its salt, solvate or solvate of the salt.

Depending on their structure, the compounds according to the inventioncan exist in stereoisomeric forms (enantiomers, diastereomers). Theinvention therefore relates to the enantiomers or diastereomers and totheir respective mixtures. Such mixtures of enantiomers and/ordiastereomers can be separated into stereoisomerically unitaryconstituents in a known manner.

The invention also relates to tautomers of the compounds, depending onthe structure of the compounds.

Salts for the purposes of the invention are preferably pharmacologicallyacceptable salts of the compounds according to the invention.Pharmacologically acceptable salts of the compounds (I) include acidaddition salts of mineral acids, carboxylic acids and sulphonic acids,for example salts of hydrochloric acid, hydrobromic acid, sulphuricacid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid,toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonicacid, acetic acid, propionic acid, lactic acid, tartaric acid, malicacid, citric acid, fumaric acid, maleic acid and benzoic acid.Pharmacologically acceptable salts of the compounds (I) also includesalts of customary bases, such as for example and preferably alkalimetal salts (for example sodium and potassium salts, alkaline earthmetal salts (for example calcium and magnesium salts) and ammonium saltsderived from ammonia or organic amines having 1 to 16 carbon atoms, suchas illustratively and preferably ethylamine, diethylamine,triethylamine, ethyldiiso-propylamine, monoethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine,dibenzylamine, N-methylmorpholine, dehydroabietylamine, arginine,lysine, ethylenediamine and methylpiperidine.Solvates for the purposes of the invention are those foul's of thecompounds that coordinate with solvent molecules to form a complex inthe solid or liquid state. Hydrates are a specific form of solvates,where the coordination is with water.For the purposes of the present invention, the substituents have thefollowing meanings, unless otherwise specified:Alkyl per se and “alk” and “alkyl” in other radicals represent a linearor branched alkyl radical having 1 to 6, or, in another embodiment, 1 to4, or in yet another embodiment 1 to 3 carbon atoms, representingillustratively methyl, ethyl, n-propyl, isopropyl, text-butyl, n-pentyland n-hexyl.Alkenyl represents a linear or branched alkyl radical having one or moredouble bonds and 2 to 6, or, in another embodiment, 2 to 4, or in yetanother embodiment 2 to 3 carbon atoms, representing illustrativelyallyl.Alkoxy represents a straight-chain or branched hydrocarbon radicalhaving 1 to 6, or, in another embodiment, 1 to 4, or in yet anotherembodiment 1 to 3 carbon atoms and bound via an oxygen atom.Non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy. The terms“alkoxy” and “alkyloxy” can be used synonymously.Alkylamino represents an amino radical having one or two (independentlyselected) alkyl substituents, illustratively representing methylamino,ethylamino, n-propylamino, isopropylamino, tert-butylamino,n-pentylamino, n-hexylamino, N,N-dimethylamino, N,N-diethylamino,N-ethyl-N-methylamino, N-methyl-N-n-propylamino,N-isopropyl-N-n-propylamino, N-t-butyl-N-methylamino,N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino.Alkenylamino represents an amino radical having one or two(independently selected) alkenyl substituents, illustrativelyrepresenting allylamino.Alkylsulfonyloxy represents *—OS(O)₂alkyl.Alkylsulfonyl represents *—S(O)₂alkylAlkoxycarbonyl represents an alkoxy radical bound via a carbonyl group,e.g. methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl andn-hexoxycarbonyl.Aryl represents a mono- to tricyclic carbocyclic radical, which isaromatic at least in one ring and bound via an oxygen atom, havinggenerally 6 to 14 carbon atoms, illustratively representing phenyl,naphthyl and phenanthrenyl.Heteroaryl represents an mono- or bicyclic radical having generally 5 to10 and preferably 5 or 6 ring atoms and up to 5 and preferably up to 4hetero atoms selected from the group consisting of nitrogen, oxygen andsulfur, which is aromatic at least in one ring. It can be attached via aring carbon atom or a ring nitrogen atom. If it represents a bicycle,wherein one ring is aromatic and the other one is not, it can beattached at both rings. Illustrative examples are thienyl, furyl,pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl,pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl,quinolinyl, isoquinolinyl.Heterocyclyl represents a mono- or polycyclic, preferably mono- orbicyclic, nonaromatic heterocyclic radical having 4 to 10, or, inanother embodiment, 5 to 8, or in yet another embodiment 5 or 6 ringatoms and up to 3, or, in another embodiment, 1 or 2 hetero atoms and/orhetero groups selected from the group consisting of nitrogen, oxygen andsulfur, SO and SO₂. It can be attached via a ring carbon atom or a ringnitrogen atom. Illustrative examples are tetrahydrofuran-2-yl,pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, piperidinyl, morpholinyl,perhydroazepinyl.Pyridylmethoxy represents a pyridyl substituent attached to the carbonatom of a methoxy group, e.g. 2-pyridylmethoxy.Halogen represents fluorine, chlorine, bromine and iodine.An asterisk (*) symbol next to a bond denotes the point of attachment inthe molecule.

The depiction of R⁷ in formula (I) with a bond directed into thearomatic pyrazole ring means that one R⁷ can be attached to one of thetwo nitrogen atoms in said aromatic pyrazole ring, i.e. either to thenitrogen atom next to the carbon atom substituted with R⁶ or to theother one.

When the conjunction “or” connects two part sentences of a claimdefining alternative definitions for a substituent which can be presentin a number larger than one, said “or” may also be interpreted as an“and”.

If radicals in the compounds according to the invention are substituted,the radicals, unless otherwise specified, can be substituted by one ormore identical or different substituents. A substitution with up tothree identical or different substituents is preferred. Very particularpreference is given to substitution with one substituent. When anitrogen-containing molecule is further substituted, the substitutionpreferably does not take place on the nitrogen atom, if suchsubstitution leads to quaternization of said nitrogen atom, e.g. in thecase of alkylation.

Except for intermediates, chemically unstable compounds are lesspreferred in the context of the present invention. The expressionchemically unstable here is meant to include conditions to which acompound is exposed when administered to a patient in need thereof, suchas acidic or basic conditions of the gastrointestinal tract. Forexample, a chemically unstable compound would be one where two nitrogenor oxygen substituents are bonded to a single aliphatic carbon atom.Another example of a chemically unstable compound would be one where analkoxy group is bonded to the unsaturated carbon of an alkene to form anenol ether. Furthermore, an aliphatic carbon atom attached to oxygen maynot also bear a chloro, bromo or iodo substituent, and when any alkylgroup is attached to O, S, or N, and bears a hydroxyl substituent, thenthe hydroxyl substituent is separated by at least two carbon atoms fromthe O, S, or N to which the alkyl group is attached.

In another embodiment, the present invention provides compounds of theformula (I),

whereinR¹ is hydrogen;R² is hydrogen;R³ is selected from the group consisting of hydrogen, halo, hydroxy,methoxy, ethoxy, n-propyloxy, i-propyloxy, trifluoromethoxy, benzyloxy,halogenated benzyloxy, pyridoxy, methylated pyridoxy, ethylatedpyridoxy, halogenated pyridoxy, pyridylmethoxy, halogenatedpyridylmethoxy, and N-morpholinyl, orR² and R³, together with the carbon atoms to which they are attached,form an pyrazole ring, wherein said pyrazole ring can optionally besubstituted with 0 or 1 substituents benzyl;R⁴ is selected from the group consisting of hydrogen, methyl, ethyl,n-propyl, i-propyl, cyano, and halo;R⁵ is hydrogen;R⁶ is hydrogen;R⁷ is selected from the group consisting of hydrogen, methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, and amino, orR⁷ is alkyl selected from the group consisting of methyl, ethyl, andn-propyl, wherein said alkyl is substituted with 1 or 2 independentlyselected substituents R⁷⁻¹, wherein R⁷⁻¹ is selected from the groupconsisting of halo, hydroxy, methoxy, ethoxy, n-propyloxy, i-propyloxy,methylsulfonyloxy, amino, orR⁷⁻¹ is alkylamino, wherein said alkylamino can optionally besubstituted with 0, 1 or 2 substituents independently selected from thegroup consisting of hydroxy, methoxy, ethoxy, n-propyloxy, i-propyloxy,amino, methylamino, ethylamino, dimethylamino, diethylamino,methylethylamino, methylsulfonyl, N-pyrrolidinyl, and N-morpholinyl, orR⁷⁻¹ is a heterocycle selected from the group consisting ofN-pyrrolidinyl, N-imidazolyl, N-morpholinyl, N-piperidinyl,N-piperazinyl, and N-thiomorpholinyl, wherein said heterocycle canoptionally be substituted with 0 or 1 substituents independentlyselected from the group consisting of methyl, ethyl, n-propyl, i-propyl,halo, hydroxy, methoxy, ethoxy, n-propyloxy, i-propyloxy, amino,methylamino, ethylamino, dimethylamino, diethylamino, methylethylamino,hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, carboxyl,methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl,i-propyloxycarbonyl, n-butyloxycarbonyl, i-butyloxycarbonyl,t-butyloxycarbonyl, N-pyrrolidinyl, N-piperidinyl, N-piperazinyl,pyrazinyl, benzyl, and pyridylmethyl;or its salt, solvate or solvate of the salt.

In another embodiment, the present invention provides compounds of theformula (I),

wherein R′, R², and R⁵ are hydrogen, R³ is 2-pyridylmethoxy and R⁴ ischloro.

In another embodiment, the present invention provides compounds of theformula (I),

wherein R¹, R², and R⁵ are hydrogen, R³ is fluoro and R⁴ is chloro.

In another embodiment, the present invention provides compounds of theformula (I), wherein R¹, R², R⁴, and R⁵ are hydrogen, and R³ is3-fluorobenzyloxy.

In another embodiment, the present invention provides a process forpreparing the compounds of the formula (I), wherein a compound offormula (II)

wherein R¹ to R⁷ have the meaning indicated above,is oxidized with a oxidising agent or oxidant, such as DDQ.

In another embodiment, the present invention provides a process forpreparing the compounds of the formula (Ic),

wherein R¹ to R⁶ have the meaning indicated above, q is 2, 3 or 4, andR″ is hydrogen, alkyl, or may be joined to form a heterocyclic ring,wherein a compound of formula

wherein R¹ to R⁶ have the meaning indicated above, q is 2, 3 or 4, and Xis halo or MsO,is reacted with a compound of formula

(R″)₂NH

wherein R″ is hydrogen, alkyl, or may be joined to form a heterocyclicring.

Accordingly, a compound of formula (II), as well as a compound offormula (Ib) are valuable precursors for making a compound of thepresent invention, and are as such also part of the present invention.

The preparation of the compounds according to the invention can beillustrated by means of the following synthetic schemes. In theseschemes, unless specifically designated otherwise, R¹-R⁷ are as definedfor formula (I) above.

In general, compounds of formula (I) can be prepared from the routeoutlined in Reaction Scheme 1. In this scheme, a mono-protectedcyclohexane-1-4-dione of formula (1) is allowed to react with acyanoacetic acid ester of formula (2) in the presence of sulfur and abase, to form the bicyclic aminothiophene carboxylic acid ester offormula (3). Reaction of this compound with either formamidine orformamide gives the tricyclic thiopyrimidone of formula (4). Reaction ofthe formula (4) compound with a halogenating agent such as POCl₃ givesthe chloro derivative of formula (5). The tricyclic compound of formula(5) is allowed to react with a substituted aniline of formula (6) in thepresence of a base and a polar solvent such as ethanol to give theintermediate of formula (7). Hydrolysis of (7) under aqueous acidicconditions provides the ketone of formula (8). Reaction of (8) with aN,N-dimethylamide dimethyl acetal, such as DMF dimethylacetal, gives anenaminone intermediate of formula (9). This intermediate is thencondensed with a hydrazine of general formula HO—(CH₂)_(q)—NHNH₂(wherein q=2, 3, or 4), to give the compound of formula (10). Oxidationof (10) using reagent such as DDQ affords the compound of formula (Ia)[(formula (1), where R⁷ is a hydroxy-substituted alkyl group]. Thisformula (Ia) compound can be converted to the corresponding formula (Ib)compound [(I), where R⁷ is haloalkyl or alkysulfonyloxyalkyl], byreaction of (Ia) with a halogenating agent such as SOBr₂ or with analkanesulfonyl chloride such as methane sulfonyl chloride. The compoundof formula (Ib) may be converted to the compound of formula (Ic) [(I),where R⁷ is alkyl substituted by R⁷⁻¹, where R⁷⁻¹ is an amino,alkylamino or heterocycle] by allowing it to react with a secondary orprimary amine, such as diethylamine or with an optionally substitutednitrogen heterocycle, such as a pyrrolidine, a piperidine, or amorpholine, provided the N-atom of the heterocycle remainsunsubstituted.

Compound (10) described in Reaction Scheme 1 may provide regioisomericmixtures in which the location of the R⁷ group may be on either nitrogenatom of the fused pyrazole ring. These regioisomers may be separated, asdesired, by standard chromatographic methods. However, Reaction Schemes2 and 3 illustrate general methods to prepare the individualregioisomers of compound (10), and their subsequent use to preparecompounds of formula (1).

In Reaction Scheme 2, the pyrazole ring-forming reaction is carried outusing the enaminone of formula (9) and a 1-hydroxyalkylhyrazinecarboxylate of general formula HO—(CH₂)_(q)—N(NH₂)—CO₂alkyl, where q is2, 3 or 4. By this method, the regioisomer of formula (10a) is prepared.Reaction of (10a) with DDQ, followed by treatment with a halogenating orsulfonylating agent in a manner analogous to that described in ReactionScheme 1, provides the regioisomer of formula (Ib-1). Reaction of (Ib-1)with (R″)₂NH gives the regioisomer of formula (Ic-1).

In Reaction Scheme 3 is illustrated the preparation of the compounds offormulae 10b, Ia-2, Ib-2 and Ic-2, examples of the other formula (I)regioisomer. The pyrazole ring-is formed in the first step of thisscheme: a doubly protected hydrazine, namely2-tert-butyldimethylsilyloxy-1-tert-butyloxycarbonyl-alkylhydrazine, isallowed to react with the compound of formula (9) to provide thecompound of formula (10b). The preparation of compounds of formula(Ia-2) and (Ib-2) is then carried out in a manner identical to thatdescribed for formula (Ia-1) and (Ib-1): The hydroxyalkylpyrazole (Ia-2)is converted to (Ib-2) by halogenation or alkylsulfonylation, and (Ib-2)is then converted to (Ie-2) by reaction with an amine of general formula(R″)₂NH.

By using these general methods and adjusting the starting materials andconditions as needed, one skilled in the art can prepare the compoundsof the invention.

Additional compounds of formula (1) can be prepared from other formula(1) compounds by elaboration of functional groups present. Suchelaboration includes, but is not limited to, hydrolysis, reduction,oxidation, alkylation, acylation, esterification, amidation anddehydration reactives. Such transformations may in some instancesrequire the use of protecting groups by the methods disclosed in T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis; Wiley:New York, (1999), and incorporated herein by reference. Such methodswould be initiated after synthesis of the desired compound or at anotherplace in the synthetic route that would be readily apparent to oneskilled in the art.

The compounds according to the invention exhibit an unforeseeable,useful pharmacological and pharmacokinetic activity spectrum. They aretherefore suitable for use as medicaments for the treatment and/orprophylaxis of disorders in humans and animals.

The compounds according to the invention are because of theirpharmacological properties useful alone or in combination with otheractive components for treating and/or preventing hyperproliferativedisorders, especially cancer.

In another embodiment, the present invention provides a medicamentcontaining at least one compound according to the invention. In anotherembodiment, the present invention provides a medicament containing atleast one compound according to the invention together with one or morepharmacologically safe excipient or carrier substances, and also theiruse for the abovementioned purposes.

The active compound can act systemically and/or locally. For thispurpose it can be administered in a suitable manner, such as for exampleby oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal,rectal, dermal, transdermal, ophtalmic or otic administration or in theform of an implant or stent. The active compound can be administered informs suitable for these modes of administration.

Suitable forms of oral administration are those according to the priorart which function by releasing the active compound rapidly and/or in amodified or controlled manner and which contain the active compound in acrystalline and/or amorphous and/or dissolved form, such as for exampletablets (which are uncoated or coated, for example with enteric coatingsor coatings which dissolve after a delay in time or insoluble coatingswhich control the release of the active compound), tablets orfilms/wafers which disintegrate rapidly in the oral cavity orfilms/lyophilisates, capsules (e.g. hard or soft gelatin capsules),dragées, pellets, powders, emulsions, suspensions and solutions.

Parenteral administration can be carried out by avoiding an absorptionstep (e.g. by intravenous, intraarterial, intracardial, intraspinal orintralumbar administration) or by including absorption (e.g. byintramuscular, subcutaneous, intracutaneous or intraperitonealadministration). Suitable parenteral administration forms are forexample injection and infusion formulations in the form of solutions,suspensions, emulsions, lyophilisates and sterile powders.

Suitable forms of administration for the other modes of administrationare for example inhalation devices (such as for example powder inhalers,nebulizers), nasal drops, solutions and sprays; tablets or films/wafersfor lingual, sublingual or buccal administration or capsules,suppositories, ear and eye preparations, vaginal capsules, aqueoussuspensions (lotions or shaking mixtures), lipophilic suspensions,ointments, creams, transdermal therapeutic systems, milky lotions,pastes, foams, dusting powders, implants or stents.

The active compounds can be converted into the abovementioned fauns ofadministration in a manner known to the skilled man and in accordancewith the prior art using inert, non-toxic, pharmaceutically suitableauxiliaries. The latter include for example excipients (e.g.microcrystalline cellulose, lactose, mannitol, etc.), solvents (e.g.liquid polyethylene glycols), emulsifiers and dispersants or wettingagents (e.g. sodium dodecyl sulphate, polyoxysorbitan oleate etc.),binders (e.g. polyvinyl pyrrolidone), synthetic and/or natural polymers(e.g. albumin), stabilizers (e.g. antioxidants, such as, for example,ascorbic acid), dyes (e.g. inorganic pigments such as iron oxides) ortaste- and/or odour-corrective agents.

In general it has proven advantageous for parenteral administration toadminister daily quantities of approximately from 0.001 to 300 mg/kgbody weight, and preferably approximately from 0.10 to 150 mg/kg bodyweight in order to obtain effective results.

It may however be necessary to deviate from the abovementionedquantities, depending on the body weight, mode of administration, theindividual patient response to the active compound, the type ofpreparation and the time or interval of administration.

The percentages in the tests and examples which follows are, unlessotherwise stated, by weight; parts are by weight. Solvent ratios,dilution ratios and concentrations reported for liquid/liquid solutionsare each based on the volume.

A. EXAMPLES Abbreviations and Acronyms

When the following abbreviations are used throughout the disclosure,they have the following meaning:

-   aq aqueous-   Boc tert-butoxycarbonyl-   CDCl₃-d chloroform-d-   CD₂Cl₂-d₄ methylene chloride-d-   CD₃OD-d₄ methanol-d₄-   Celite® brand of diatomaceous earth, Celite Corporation-   d doublet-   dd double doublet-   DDQ 2,3-dichloro-5,6-dicyanobenzoquinone-   DMF N,N-dimethyl formamide-   DMSO-d₆ dimethylsulfoxide-d₆-   EtOAc ethyl acetate-   EtOH ethanol-   equiv equivalent(s)-   h hour(s)-   ¹H NMR proton nuclear magnetic resonance-   HPLC high performance liquid chromatography-   LCMS liquid chromatography/mass spectroscopy-   min minute(s)-   Me methyl-   MeOH methanol-   MS mass spectrometry-   Ms methanesulfonyl (mesyl)-   rt room temperature-   RT retention time (HPLC)-   s singlet-   t triplet-   td triple doublet-   TFA trifluoroacetic acid

General Analytical Procedures

The structure of representative compounds of this invention wereconfirmed using the following procedures.

Electron impact mass spectra (EI-MS) were obtained with a HewlettPackard® 5989 A mass spectrometer equipped with a Hewlett Packard® 5890Gas Chromatograph with a J & W DB-5 column (0.25 uM coating; 30 m×0.25mm). The ion source is maintained at 250° C. and spectra were scannedfrom 50-800 amu at 2 sec per scan.

High pressure liquid chromatography-electrospray mass spectra (LC-MS)were obtained using either a:

(A) Hewlett-Packard® 1100 HPLC equipped with a quaternary pump, avariable wavelength detector set at 254 nm, a YMC pro C-18 column (2×23mm, 120 A), and a Finnigan® LCQ ion trap mass spectrometer withelectrospray ionization. Spectra were scanned from 120-1200 amu using avariable ion time according to the number of ions in the source. Theeluents were A: 2% acetonitrile in water with 0.02% TFA and B: 2% waterin acetonitrile with 0.018% TFA. Gradient elution from 10% B to 95% over3.5 minutes at a flow rate of 1.0 mL/min is used with an initial hold of0.5 minutes and a final hold at 95% B of 0.5 minutes. Total run time is6.5 minutes.or(B) Gilson® HPLC system equipped with two Gilson 306 pumps, a Gilson 215Autosampler, a Gilson® diode array detector, a YMC Pro C-18 column (2×23mm, 120 A), and a Micromass LCZ single quadrupole mass spectrometer withz-spray electrospray ionization. Spectra were scanned from 120-800 amuover 1.5 seconds. ELSD (Evaporative Light Scattering Detector) data isalso acquired as an analog channel. The eluents were A: 2% acetonitrilein water with 0.02% TFA and B: 2% water in acetonitrile with 0.018% TFA.Gradient elution from 10% B to 90% over 3.5 minutes at a flowrate of 1.5mL/min is used with an initial hold of 0.5 minutes and a final hold at90% B of 0.5 minutes. Total run time is 4.8 minutes. An extra switchingvalve is used for column switching and regeneration.

Routine one-dimensional ¹H NMR spectroscopy is performed on 300 MHzVarian® Mercury-plus spectrometers. The samples were dissolved indeuterated solvents obtained from Cambridge Isotope Labs®, andtransferred to 5 mm ID Wilmad® NMR tubes. The spectra were acquired at293 K. The chemical shifts were recorded on the ppm scale and werereferenced to the appropriate solvent signals, such as 2.49 ppm forDMSO-d₆, 1.93 ppm for CD₃CN-d₃, 3.30 ppm for CD₃OD-d₄, 5.32 ppm forCD₂Cl₂-d₄ and 7.26 ppm for CDCl₃-d for ¹H spectra.

EXAMPLE 1 Preparation of2-[6-(3-Chloro-4-fluoro-phenylamino)-10-thia-2,3,7,9-tetraazacyclopenta[a]fluoren-2-yl]-ethanol

Step 1. Preparation of Ethyl2-amino-4,7-dihydro-5H-spiro[1-benzothiophene-6,2′-[1,3]dioxolane]-3-carboxylate

To 600 mL ethanol were sequentially 1,4-dioxa-spiro[4.5]decan-8-one(25.0 g, 0.160 mol), ethyl cyanoacetate (18.1 g, 0.160 mol), morpholine(14.0 g, 0.160 mol), and sulfur (5.5 g, 0.160 mol). The heterogeneouscontents were stirred at room temperature for 4 days, after which timeall the sulfur had dissolved. The homogeneous contents were concentratedunder reduced pressure, and the residue diluted with EtOAc (200 mL). Themixture was washed with water (200 mL), and the layers were separated.The organic layer was dried over MgSO₄, filtered, and concentrated underreduced pressure to afford the desired product as a dark colored oil(45.0 g, 99%). ¹H-NMR (DMSO-d₆) δ 7.20 (s, 2H), 4.10 (q, 2H), 3.87 (s,4H), 2.66 (t, 2H), 2.59 (s, 2H), 1.71 (t, 2H), 1.18 (t, 3H); LCMSRT=2.58 min; [M+H]⁺=284.2.

Step 2. Preparation of3,5,6,8-tetrahydro-4H-spiro[1-benzothieno[2,3-d]pyrimidine-7,2′-[1,3]dioxolan]-4-one

To a stirring solution of ethyl2-amino-4,7-dihydro-5H-spiro[1-benzothiophene-6,2′-[1,3]dioxolane]-3-carboxylate(40.0 g, 0.142 mol) in formamide (225 mL) was added ammonium formate(17.8 g, 0.282 mol). The resulting mixture was stirred with at 140° C.for 16 h, after which time the heterogeneous contents were removed fromheating, and allowed to cool to rt. The contents were filtered, thesolid filter cake was washed with water (2×60 mL), and suction driedovernight to afford the desired product as an off-white solid (33.0 g,88%). ¹H-NMR (DMSO-d₆) δ 12.35 (broad s, 1H), 8.00 (s, 1H), 3.92 (s,4H), 2.95 (t, 2H), 2.91 (s, 2H), 1.83 (t, 2H); LCMS RT=1.87 min;[M+H]⁺=265.2.

Step 3. Preparation of4-chloro-5,8-dihydro-6H-spiro[1-benzothieno[2,3-d]pyrimidine-7,2′-[1,3]dioxolane]

To a stirring solution of3,5,6,8-tetrahydro-4H-spiro[1-benzothieno[2,3-d]pyrimidine-7,2′-[1,3]dioxolan]-4-one(20.0 g, 0.076 mol) in POCl₃ (200 mL) at 0° C. was added triethylamine(200 mL) over a 15 min period. The resulting mixtures were allowed towarm to rt, and then heated to 80° C. After 3 h, the contents wereremoved from heating, and allowed to cool to rt. The heterogeneousmixture was concentrated under reduced pressure. The residue was dilutedwith EtOAc (100 mL), and concentrated again to further remove thevolatile materials. The residue was then diluted with EtOAc (100 mL) andthe heterogeneous mixture poured onto a stirring mixture of ice-water/aqNaHCO₃ (800 mL). After 5 min stirring, the contents (pH≈7) were filteredand the solid filter cake washed with water. The product was dried invacuum oven overnight to afford the desired product (20.7 g, 97%) as anoff-white solid. ¹H-NMR (DMSO-d₆) δ 8.82 (s, 1H), 3.97 (s, 4H), 3.10 (t,2H), 3.07 (s, 2H), 1.95 (t, 2H); LCMS RT=2.45 min; [M+H]⁺=−283.1.

Step 4. Preparation ofN-(3-chloro-4-fluorophenyl)-5,8-dihydro-6H-spiro[1-benzothieno[2,3-d]pyrimidine-7,2′-[1,3]dioxolan]-4-amine;

To a stirring solution of4-chloro-5,8-dihydro-6H-spiro[1-benzothieno[2,3-d]pyrimidine-7,2′-[1,3]-dioxolane](7.0 g, 24.8 mmol) in ethanol (100 mL) was added4-fluoro-3-chloroaniline (3.6 g, 24.8 mmol) and HCl (4N in dioxane, 0.05mL). The contents were heated to reflux for 5 h, after which time thecontents were removed from heating and allowed to cool to rt. Thesolvent was removed under reduced pressure, the crude residue suspendedin aq NaHCO₃ (100 mL), and stirred for 15 min. The contents were againfiltered, and the solid filter cake washed with water. The collectedyellow solid was triturated with diethyl ether (50 mL) to afford thefinal product (5.5 g, 57%) as a light yellow solid. ¹H-NMR (DMSO-d₆) δ8.41 (s, 1H), 8.28 (s, 1H), 7.78 (dd, 1H), 7.58 (m, 1H), 7.35 (t, 1H),3.97 (s, 4H), 3.22 (t, 2H), 3.00 (s, 2H), 1.93 (t, 2H); LCMS RT=3.26min; [M+H]⁺=392.3.

Step 5. Preparation of4-(3-Chloro-4-fluoro-phenylamino)-5,8-dihydro-6H-benzo[4,5]thieno[2,3-d]pyrimidin-7-one

To a stirring acetic acid/water solution (4:1, 300 mL) was addedN-(3-chloro-4-fluorophenyl)-5,8-dihydro-6H-spiro[1-benzothieno[2,3-d]pyrimidine-7,2′-[1,3]dioxolan]-4-amine(5.5 g, 14 mmol), and the contents heated at 80° C. for 12 h. The darkcolored mixture was cooled to rt, and the solvent was removed underreduced pressure. The crude residue was suspended in aq NaHCO₃ (1N, 100mL), stirred for 10 min, and filtered. The filtered solid was trituratedwith diethyl ether (100 mL) to afford the desired product (4.8 g, 98%)as a dark yellow solid. ¹H-NMR (DMSO-d₆) δ 8.53 (s, 1H), 8.46 (s, 1H),7.87 (dd, 1H), 7.60 (m, 1H), 7.40 (t, 1H), 3.73 (s, 2H), 3.43 (t, 2H),2.64 (s, 2H); LCMS RT=3.01 min; [M+H]⁺=348.2.

Step 6. Preparation of4-(3-Chloro-4-fluoro-phenylamino)-8-dimethylaminomethylene-5,8-dihydro-6H-benzo[4,5]thieno[2,3-d]pyrimidin-7-one

A slurry of4-(3-chloro-4-fluoro-phenylamino)-5,8-dihydro-6H-benzo[4,5]thieno[2,3-d]pyrimidin-7-one(8.0 g, 0.023 mol) in toluene (80 mL) was prepared andN,N-dimethylformamide dimethyl acetal (3.2 mL, 0.024 mol) was added. Theorange slurry turned dark purple upon heating in an oil bath at 80° C.After 1 h the solvent was evaporated in vacuo to yield a medium brownsolid that was carried on directly to the next step. LCMS RT=3.06 min;[M+H]⁺=403.2.

Step 7. Preparation of2-{6-[(3-chloro-4-fluorophenyl)amino]-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-2-yl}ethanol

To a stirred solution of4-(3-chloro-4-fluoro-phenylamino)-8-dimethylaminomethylene-5,8-dihydro-6H-benzo[4,5]thieno[2,3-d]pyrimidin-7-one(0.023 mol) in ethanol (93 mL) was added hydroxyethyl hydrazine (2.14 g,0.024 mol). The slurry was heated in an oil bath at 50° C. for 3 h andthen allowed to cool to room temperature overnight. The reaction mixturewas filtered and the resulting solid was dried by vacuum filtration on aBuchner funnel for 2 h to yield an orange powdery solid (7.68 g, 80%).¹H NMR indicates a mixture of regioisomers (3:2 in favor of example 1).The above batch (7.2 g) of alcohol was combined with another batch (3.0g, 3:1 regioisomer ratio in favor of example 1) and heated to nearhomogeneity in methoxybenzene (250 mL) at reflux. The mixture was cooledto 80° C. and EtOH (100 mL) was added while maintaining the internaltemperature at about 80° C. The mixture was allowed to cool to roomtemperature with stirring. An orange solid precipitated and wascollected by vacuum filtration (8.5 g, 7:3 regioisomer ratio in favor ofexample 1). The collected solid was transferred into a flask, reheatedto reflux with methoxybenzene (300 mL), cooled to about 80° C., anddiluted with EtOH (150 mL). The mixture was allowed to cool to roomtemperature overnight. The orange solid was collected by vacuumfiltration (3.8 g, 93% regioisomeric purity by LC). ¹H NMR (DMSO-d₆) δ8.58 (s, 1H), 8.39 (s, 1H), 7.94 (s, 1H), 7.88 (m, 1H), 7.61 (m, 1H),7.40 (t, 1H), 4.93 (t, 1H), 4.11 (t, 2H), 3.75 (dt, 2H), 3.39 (t, 2H),2.94 (t, 2H); LCMS RT=2.78 min; [M+H]⁺=416.4.

Step 8. Preparation of2-[6-(3-Chloro-4-fluoro-phenylamino)-10-thia-2,3,7,9-tetraazacyclopenta[a]fluoren-2-yl]-ethanol

To a stirring solution of2-{6-[(3-chloro-4-fluorophenyl)amino]-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-c]indazol-2-yl}ethanol(2.6 g, 6.25 mmol) in dioxane (25 mL) was added2,3-dichloro-5,6-dicyanobenzoquinone (2.1 g, 9.38 mmol). The reactionmixture was heated to 90° C. for 2.5 h. The solid was filtered andseparated by column chromatograph (90% methylene chloride/10% methanol)to give2-[6-(3-chloro-4-fluoro-phenylamino)-10-thia-2,3,7,9-tetraazacyclopenta[a]fluoren-2-yl]-ethanolas a brown solid (3.0 g, yield 116% containing some carried over silicagel). ¹H-NMR (DMSO-d₆) δ 9.25 (bs, 1H), 8.80 (s, 1H), 8.60 (s, 1H), 8.40(t, 1H), 7.90 (d, 1H), 7.80 (d, 1H), 7.60 (m, 1H), 7.40 (t, 1H), 4.50(t, 2H), 3.90 (t, 2H); LCMS RT=2.95 min; [M+H]⁺=414.2.

EXAMPLE 2 Preparation of Methanesulfonic acid2-[6-(3-chloro-4-fluoro-phenylamino-10-thia-2,3,7,9-tetraaza-cyclopenta[a]fluoren-2-yl]-ethylester

To a stirring solution of2-[6-(3-chloro-4-fluoro-phenylamino)-10-thia-2,3,7,9-tetraazacyclopenta[a]fluoren-2-yl]-ethanol(2.53 g, 6.11 mmol) in acetonitrile (60 mL) was added methane sulfonicanhydride (2.1 g, 12.23 mmol) and pyridine (0.965 g, 12.23 mmol). It wasstirred at room temperature for 2 h. The solid was filtered and furthertriturated with diethyl ether, oven dried overnight to givemethanesulfonic acid2-[6-(3-chloro-4-fluoro-phenylamino)-10-thia-2,3,7,9-tetraaza-cyclopenta[a]fluoren-2-yl]-ethylester as brown solid (2.0 g, 66.5%). ¹H-NMR (DMSO-d₆) δ 9.30 (bs, 1H),8.90 (s, 1H), 8.80 (t, 1H), 8.40 (d, 1H), 7.90 (m, 1H), 7.80 (d, 1H),7.60 (m, 1H), 7.40 (t, 1H), 5.00 (t, 2H), 3.90 (t, 2H), 3.80 (s, 3H);LCMS RT=3.29 min; [M+H]⁺=492.1.

EXAMPLE 3 Preparation of(3-Chloro-4-fluoro-phenyl)-{2-[2-(2-methanesulfonyl-ethylamino)-ethyl]-2H-10-thia-2,3,7,9-tetraaza-cyclopenta[a]fluoren-6-yl}-amine

To a stirring solution of methanesulfonic acid2-[6-(3-chloro-4-fluoro-phenylamino)-10-thia-2,3,7,9-tetraaza-cyclopenta[a]fluoren-2-yl]-ethylester (190 mg, 0.39 mmol) in DMF (3 mL) was added diisopropylethylamine(99 mg, 0.77 mmol) and 2-aminoethylmethylsulfone (143 mg, 1.16 mmol). Itwas heated to 80° C. for overnight. The crude mixture was diluted withmethanol (5 mL) and it was separated by prep HPLC. The prep HPLCfractions were collected and solvent was removed by vacuum. The solidwas re-dissolved by ethyl acetate (15 mL) and water (10 mL), sat. sodiumcarbonate solution (3 mL) was added. The organic layer was separated anddried over sodium sulfate. Evaporation of the solvents gave(3-chloro-4-fluoro-phenyl)-{2-[2-(2-methanesulfonyl-ethylamino)-ethyl]-2H-10-thia-2,3,7,9-tetraaza-cyclopenta[a]fluoren-6-yl}-amineas a white solid (10.3 mg, 5.1%) ¹H-NMR (DMSO-d₆) δ 9.25 (bs, 1H), 8.80(d, 1H), 8.60 (d, 1H), 8.40 (t, 1H), 7.90 (d, 1H), 7.80 (d, 1H), 7.60(t, 1H), 7.40 (t, 1H), 4.60 (t, 2H), 3.20 (t, 2H), 2.90 (s, 3H), 2.10(t, 2H), 2.05 (t, 2H); LCMS RT=2.89 min.; [M+H]⁺=519.2.

EXAMPLE 21 Preparation of2-[6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-3H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-3-yl]ethanol

Step 1. Preparation ofN-(3-Chloro-4-(3-fluoro-benzyloxy)-phenylamine)-5,8-dihydro-6H-spiro[1-benzothieno[2,3-d]pyrimidine-7,2′-[1,3]dioxolan]-4-amine

To 2-propanol (300 mL) were sequentially added4-chloro-5,8-dihydro-6H-spiro[1-benzothieno[2,3-d]pyrimidine-7,2′-[1,3]dioxolane](20.7 g, 73.2 mmol), 3-Chloro-4-(3-fluoro-benzyloxy)-phenylamine (18.4g, 73.2 mmol), and HCl in dioxane (4N, 0.92 mL). The suspension wasstirred with heating to 80° C., upon which the contents turn brown andhomogeneous. After 15 h, the dark orange-yellow heterogeneous mixturewas removed from heating, and allowed to cool to rt. The contents werefiltered and the collected solid product dried under vacuum. Thefiltrate was concentrated under reduced pressure and the residuesuspended in CH₃OH (50 mL), upon which formation of a second crop ofproduct ensues. The second crop was collected, and from this filtrate athird crop could also be obtained. The solid product crops were combinedto afford the final product (33.5 g, 92%) as an off-white solid. ¹H-NMR(DMSO-d₆) δ 1.90 (t, 2H), 3.00 (s, 2H), 3.26 (t, 2H), 3.97 (s, 4H), 5.22(s, 2H), 7.11-7.30 (m, 4H), 7.41-7.55 (m, 2H), 7.74 (s, 1H), 8.33 (s,1H), 8.39 (s, 1H); LCMS RT=3.63 min; [M+H]⁺=498.3.

Step 2. Preparation ofN-(3-Chloro-4-(3-fluoro-benzyloxy)-phenylamine)-5,8-dihydro-6H-benzo[4,5]thieno[2,3-d]pyrimidin-7-one

To a stirring acetic acid/H₂O solution (4:1, 600 mL) was addedN-(3-chloro-4-(3-fluoro-benzyloxy)-phenylamine)-5,8-dihydro-6H-spiro[1-benzothieno[2,3-d]pyrimidine-7,2′-[1,3]dioxolan]-4-amine(34.8 g, 69.8 mmol), and the contents heated at 80° C. for 16 h. Thedark colored mixture was cooled to rt, and the solvent removed underreduced pressure. The crude residue was suspended in 1N NaHCO₃ aqsolution (500 mL), stirred for 10 min, and filtered. The collected solidwas again vigorously washed with H₂O (500 mL) and filtered to afford thedesired product, which was vacuum dried with heating at 40° C. for 24 h.The final product was collected (30.8 g, 97%) as an orange solid. ¹H-NMR(DMSO-d₆) δ 2.66 (t, 2H), 3.44 (t, 2H), 3.74 (s, 2H), 5.23 (s, 2H),7.14-7.32 (m, 4H), 7.40-7.52 (m, 2H), 7.75 (d, 1H), 8.34 (s, 1H), 8.39(s, 1H); LCMS RT=3.50 min; [M+H]⁺=454.1.

Step 3. Preparation ofN-(3-Chloro-4-(3-fluoro-benzyloxy)-phenylamine)-8-dimethylaminomethylene-5,8-dihydro-6H-benzo[4,5]thieno[2,3-d]pyrimidin-7-one

To 150 mL toluene were addedN-(3-chloro-4-(3-fluoro-benzyloxy)-phenylamine)-5,8-dihydro-6H-benzo[4,5]thieno[2,3-d]pyrimidin-7-one(9.6 g, 18 mmol) and dimethylformamide-dimethylacetal (4.78 mL, 36mmol). The contents were stirred at 70° C. for 4 h, after which timethey were allowed to cool to rt. The heterogeneous mixture was filtered,collected solid washed with acetone (5 mL), and dried under hi-vac. Thefinal product was collected (7.0 g, 70%) as a yellow solid. ¹H-NMR(DMSO-d₆) (major rotamer) δ 2.53 (t, 2H), 3.10 (s, 6H), 3.24 (t, 2H),5.21 (s, 2H), 7.10-7.21 (m, 3H), 7.26-7.33 (m, 2H), 7.40-7.50 (m, 2H),7.75 (s, 1H), 8.15-8.40 (broad s, 1H), 8.30 (s, 1H); LCMS RT=3.75 min;[M+H]⁺=509.2.

Step 4. Preparation of2-[6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-4,5-dihydro-3H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-3-yl]ethanol

To 200 mL ethanol were addedN-(3-chloro-4-(3-fluoro-benzyloxy)-phenylamine)-8-dimethylaminomethylene-5,8-dihydro-6H-benzo[4,5]thieno[2,3-d]pyrimidin-7-one(12.0 g, 23.6 mmol), and then2-tent-butyloxycarbonyl-2-hydroxyethylhydrazine (6.23 g, 35.4 mmol) as a50 mL ethanol solution via dropping funnel over a 5 minute period. Thereactants were stirred at reflux for 24 h, after which time they wereremoved from heating and allowed to cool to rt. The heterogeneousmixture was then cooled to 0° C. and a light tan solid was removed byfiltration, dried under hi-vac to provide 9.8 g (65%) of solid. Thissolid was then dissolved in CH₂Cl₂ (100 mL) and cooled to 0° C. To thestirring suspension was added TFA (60 mL, 99%) via dropping funnel overa 15 minute period, during which time the contents become dark brown andhomogeneous. The mixture was stirred with warming to rt over a 12 hperiod. The contents were concentrated to about 10% of its originalvolume, diluted with CH₂Cl₂/H₂O (100 mL, 2:1), and stirred with coolingto 0° C. To the stirring mixture was added 175 mL aq 1N NaOH, to afforda pH=10 mixture which becomes heterogeneous on complete addition ofbase. The heterogeneous mixture was filtered and the filter cake washedwith water. The collected solid was recrystallized from ethanol tofurnish the final product (4.0 g, 67%, 44% for the two steps) as a lighttan solid. ¹H-NMR (DMSO-d₆) δ 3.02 (t, 2H), 3.33 (t, 2H), 3.66 (m, 2H),4.12 (m, 2H), 4.87 (m, 1H), 5.24 (s, 2H), 7.10-7.30 (m, 4H), 7.40-7.53(m, 2H), 7.61 (s, 1H), 7.73 (s, 1H), 8.31 (s, 1H), 8.38 (s, 1H); LCMSRT=3.30 min; =522.1.

Step 5. Preparation of2-[6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-3H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-3-yl]ethanol

To a stirring solution of2-[6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-4,5-dihydro-3H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-3-yl]ethanol(100 mg, 0.19 mmol) in dioxane (1 mL) was added2,3-dichloro-5,6-dicyanobenzoquinone (65 mg, 0.29 mmol). The reactionmixture was heated to 90° C. for 2.5 h. The solid was filtered andseparated by column chromatograph (90% methylene chloride/10% methanol)to give the desired product with some impurity (about 75% purity byLCMS). It was then recrystallized in methanol to give pure2-[6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-3H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-3-yl]ethanolas a brown solid (7.5 mg, yield 7.5%). ¹H-NMR (DMSO-d₆) δ 9.10 (s, 1H),8.50 (d, 2H), 8.45 (s, 1H), 7.90 (d, 1H), 7.80 (s, 1H), 7.50 (d, 1H),7.45 (m, 1H), 7.35-7.20 (m, 4H), 5.25 (s, 2H), 4.90 (bs, 1H), 4.60 (t,2H), 3.80 (t, 2H); LCMS RT=3.45 min; [M+H]⁺=520.2.

Preparation of Intermediates Preparation of tert-butyl1-(2-hydroxyethyl)hydrazinecarboxylate

The title compound was prepared according to the literature (Krapcho, A.P. J. Heterocyclic Chem. 2000, 37, 47. ¹H-NMR (CDCl₃) δ 3.81 (t, 2H),3.73 (br, 3H), 3.57 (t, 2H), 1.48 (s, 9H); LCMS RT=1.74 min @ 100%aqueous; [M+H]⁺=176.9.

Preparation of2-tert-butyldimethylsilyloxy-1-tert-butyloxycarbonyl-ethylhydrazine

To 300 mL toluene were added (tert-butyldimethylsilyloxy)acetaldehyde(9.6 g, 49.6 mmol) and tert-butylcarbazate (6.75 g, 49.6 mmol). Themixture was stirred at 65° C. for 12 h, after which time the contents,were removed from heating and allowed to cool to rt. The solvent wasremoved under reduced pressure to afford a colorless viscous oil (14.2g, 97%). This oil was dissolved in ethanol (220 mL), the solutiontransferred to a 1 L Parr vessel, and 2.84 g Pd/C (10%) were added. Themixture was hydrogenated in a Parr shaker at 50 psi of H₂ atmosphere for15 h. The contents were filtered through a thin pad of Celite® to removethe catalyst, and the filtrate concentrated in vacuo to afford the finalproduct (14 g, 98%) as a white solid. ¹H-NMR (CD₂Cl₂) δ 0.06 (s, 6H),0.90 (s, 9H), 1.43 (s, 9H), 2.90 (t, 2H), 3.69 (t, 2H), 4.16 (br, II-I),6.34 (br, 1H); LCMS RT=3.11 min; [M+H]⁺=290.8.

Preparation of 3-Chloro-4-(3-fluoro-benzyloxy)-phenylamine

To 90 mL CH₃CN was added 2-chloro-4-nitrophenol (15 g, 86.4 mmol)followed by potassium carbonate (17.9 g, 129.6 mmol). To the stirringsuspension was added via dropping funnel a 10 mL CH₃CN solution of3-fluoro-benzylbromide (16.3 g, 86.4 mmol). The contents were stirredand heated at 70° C. for 18 h, after which time the bright yellowmixture was allowed to cool to rt. The yellow contents were poured ontoH₂O (200 mL) and stirred, upon which solid formation occurs. The solidwas filtered and filter cake washed with additional H₂O (50 mL). Thecollected solid was dried in vacuo, yielding2-chloro-1-(3-fluoro-benzoyloxy)-4-nitro-benzene (23 g, 94%) as a whitesolid.

2-Chloro-1-(3-fluoro-benzoyloxy)-4-nitro-benzene (10 g, 35.5 mmol) wassuspended in 50 mL acetic acid and 150 mL EtOAc in a 500 mL flask. Iron(9.9 g (177.5 mmol) was added to this suspension, and the mixturestirred at rt overnight. The reaction mixture was filtered through athin pad of Celite®. The filtrate was concentrated in vacuo andneutralized with saturated Na₂CO₃ aq solution, followed by EtOAcextraction. The organic layer was washed with brine, dried over Na₂SO₄,and concentrated in vacuo. The resulting crude material was purified byflash chromatography eluting with 15% EtOAc/hexanes yielding3-chloro-4-(3-fluoro-benzyloxy)-phenylamine as a brown solid [8.5 g,95%, TLC R_(f)=0.4, 30% EtOAc/HEX. (3:7)]. ¹H-NMR (DMSO-d₆) δ 4.94 (s,2H), 5.00 (s, 2H), 6.40 (dd, 1H), 6.60 (s, 1H), 6.87 (d, 1H), 7.10-7.18(m, 1H), 7.20-7.28 (m, 2H), 7.37-7.44 (m, 1H).

Preparation of 3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamine

2-Chloro-4-nitro phenol 10 g (57.6 mmol, 1 eq), 2-(chloromethyl)pyridinehydrogen chloride 9.45 g (57.6 mmol, 1 equiv), cesium carbonate (41.3 g,126.8 mmol, 2.2 equiv) and sodium iodide 8.64 g (57.6 mmol, 1 equiv)were suspended in 200 mL acetonitrile. The reaction mixture was stirredat 60° C. for 5 h. The resulted suspension was filtered and washed with400 mL water, yielding 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8 g,52%) as a red solid.

2-(2-Chloro-4-nitro-phenoxymethyl)-pyridine (8 g, 30.2 mmol, 1 equiv)and 8.44 g iron (151.1 mmol, 5 equiv) in 100 mL acetic acid and 50 mLEtOAc were stirred at rt overnight. The reaction mixture was filteredthrough a pad of Celite®. The filtrate was concentrated in vacuo andneutralized with saturated Na₂CO₃ solution. The solution was extractedwith EtOAc and the organic layer was washed with brine and concentratedin vacuo. The resulting crude material was purified by flashchromatography eluting with EtOAc/hexane (3:7) to give3-chloro-4-(pyridin-2-ylmethoxy)-phenylamine (3.2 g, 52%) as a whitesolid. ¹H-NMR (CDCl₃) δ 5.18 (s, 2H), 6.50 (dd, 1H), 6.76 (d, 1H), 6.80(d, 1H), 7.22 (m, 1H), 7.64 (d, 1H), 7.73 (td, 1H), 8.55 (m, 1H); LCMSRT=0.89 min; [M+H]⁺=235.1.

By using the methods described above, or methods analogous thereto, andby substituting the appropriate starting materials, other examples ofthe invention were prepared. Examples are summarized in Table 1 below.

TABLE 1 LCMS LCMS RT Ion Ex. No. Structure (min) [M + H]+ IUPAC Name 1

2.95 414.2 2-{6-[(3-chloro-4- fluorophenyl)amino]-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol- 2-yl}ethanol 2

3.29 492.1 2-{6-[(3-chloro-4- fluorophenyl)amino]-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol- 2-yl}ethyl methanesulfonate 3

2.89 519.2 N-(3-chloro-4-fluorophenyl)-2-(2-{[2-(methylsulfonyl)ethyl]amino}ethyl)-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol- 6-amine 4

2.67 510.3 N-(3-chloro-4-fluorophenyl)-2-{2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]ethyl}-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol- 6-amine 5

2.23 526.3 N-(3-chloro-4-fluorophenyl)-2-{2-[(2-morpholin-4-ylethyl)amino]ethyl}-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol- 6-amine 6

2.91 499.2 N-(3-chloro-4-fluorophenyl)-2-{2-[(2-methoxyethyl)amino]ethyl}-2H- pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6-amine 7

2.43 457.1 2-[(2-{6-[(3-chloro-4- fluorophenyl)amino]-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol- 2-yl}ethyl)amino]ethanol 8

2.66 529.1 2-{2-[bis(2-methoxyethyl)amino]ethyl}-N-(3-chloro-4-fluorophenyl)-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6- amine 9

2.49 483.2 N-(3-chloro-4-fluorophenyl)- 2-(2-morpholin-4-ylethyl)-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol- 6-amine 10

2.45 482.1 N-(3-chloro-4-fluorophenyl)- 2-(2-piperazin-1-ylethyl)-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6- amine 11

2.48 496.1 N-(3-chloro-4-fluorophenyl)-2-[2-(4-methylpiperazin-1-yl)ethyl]-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6- amine 12

2.85 448.3 N-(3-chloro-4-fluorophenyl)-2-[2-(1H-imidazol-1-yl)ethyl]-2H- pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6-amine 13

2.67 510.3 N-(3-chloro-4-fluorophenyl)-2-{2-[(3S)-3-(dimethylamino)pyrrolidin- 1-yl]ethyl}-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol- 6-amine 14

2.3 501.3 2,2′-[(2-{6-[(3-chloro-4- fluorophenyl)amino]-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol- 2-yl}ethyl)imino]diethanoltrifluoroacetate (salt) 15

2.54 540.4 N-(3-chloro-4-fluorophenyl)-2-{2-[4-(2-methoxyethyl)piperazin-1-yl]ethyl}-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6- amine 16

2.59 481.4 N-(3-chloro-4-fluorophenyl)- 2-(2-piperidin-1-ylethyl)-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6- amine 17

2.5 467.4 N-(3-chloro-4-fluorophenyl)- 2-(2-pyrrolidin-1-ylethyl)-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6- amine 18

2.29 573.2 N-(3-chloro-4-fluorophenyl)-2-{2-[4-(pyridin-4-ylmethyl)piperazin-1- yl]ethyl}-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol- 6-amine 19

2.55 485.4 N-(3-chloro-4-fluorophenyl)-2-{2-[(2-methoxyethyl)(methyl)amino]ethyl}-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6- amine 20

2.69 510.2 N-(3-chloro-4-fluorophenyl)-3-{2-[(3S)-3-(dimethylamino)pyrrolidin- 1-yl]ethyl}-3H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6- amine 21

3.45 520.2 2-[6-({3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}amino)-3H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-3- yl]ethanol 22

2.98 565 3-(2-bromoethyl)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-3H- pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6- amine

B. EVALUATION OF PHYSIOLOGICAL ACTIVITY

The utility of the compounds of the present invention can beillustrated, for example, by their activity in vitro in the in vitrotyrosin kinase inhibition assay described below.

In Vitro Tyrosin Kinase Inhibition Assay

The ability of compounds in the present invention to inhibit thetyrosine kinase activities of EGFR (erbB1) and HER2 (erbB2) in cellularsystems was measured using ELISA (Enzyme-Linked Immunosorbent Assay)shown below.

Inhibition of Tyrosine Phosphorylation of HER1 in A431 Cells Materials:

Essentially fatty acid free Bovine Albumin: SIGMA #A9205 30% solution96-well tissue culture treated plate96-well EIA/RIA plates: Corning Costar #9018BSA for blocking Kirkegaard & Perry: #50-61-00DPBS w/o calcium and magnesium: Gibco/Invitrogen #14190

Wash Buffer: TBS/0.05% Tween RhEGF: Gibco/Invitrogen 313427-051

Her-1 Ab: Upstate Anti-EGF receptor (neutralizing) mouse monoclonal IgGclone

LA1 #05-101.

Biosource phospho-specific Anti-EFG receptor (pY1068): #44-788GAmersham Biosciences ECL Anti-rabbit IgG peroxidase-linked antibody:#NA934

TMB Substrate:Sigma #T-8665

Lysis Buffer (kept on ice):

TBS 1% Triton X-100 1 mM EDTA

1 mM Sodium orthovanadate10 mM Beta glycerol phosphate

1 mM Sodium Fluoride

10 μg/ml Aprotinin1× Roche Complete EDTA-free protease inhibitor cocktail (1 tablet/2 mLH₂O=25×)Method: Note: All antibody plate washes were performed with platewasher.

EGF was performed using a Zymark auto liquid handler unit.

Day 1

Plate 30K A431 cells/well in serum-containing media in 96-well plate.

Incubate at 37° C.

Antibody Plates: Dilute Her-1 neutralizing antibody in PBS to a finalconcentration of 1 ug/mL.Add 100 μL/well to 96-well EIA/RIA plates. Incubate overnight at 4° C.on rotator.

Day 2

BSA block antibody plates: Make stock of TBST containing 3% KPL BSA.Wash plates 3×200 μL/well with TBST. Add 100 μL/well TBST/3% BSA.Incubate at 37° C. for at least one hour.Make stock of basal media containing 0.1% BSA and sterile filter.Wash plates 2×100 μL/well with basal media and add 100 μL/well basalmedia/0.1% BSA.

Incubate at 37° C. for 2 h.

Create master compound dilution plate at concentrations 3-fold finalconcentrations. Initial concentration is in 0.1% BSA/Media. Subsequentdilutions performed in 0.1% BSA/Media containing 0.3% DMSO to match thatfound in the initial drug concentration. Keep two columns without drugfor drug free comparison. These columns should contain media/0.1%BSA/DMSO only. Transfer 50 μL/well to cell plate containing 0.1% BSA/Media.

Incubate at 37° C. for 2 hrs.

EGF Stimulation: Make 500 ng/ml stock of rhEGF (10×) in 0.1% BSA/Media.Keeping one drug-free column unstimulated, add 15 μL/well to rest ofcell plate (50 ng/ml final).For each compound, add to entire series of drug concentration at sametime to insure equal stimulation time for all concentrations for thatcompound. Incubate 5 min at r.t. with periodic swirling. Immediatelyplace on ice 5 min.Remove media and wash plate 2×150 uL/well with cold DPBS. Add 150μL/well cold Lysis Buffer containing protease inhibitors. Incubate onice 30 min rotating.Antibody coated plates: wash plates 3×200 μL/well with TBST. Transfer100 μL/well lysate to antibody coated plate. Incubate 4° C. overnightrotating.

Day 3

Wash plate 3×200 μL/well with TBST and add 100 μL/well EGFR phosphospecific Ab diluted to Ab 100 ng/ml diluted/ml TBS/3% BSA. Incubate onrotator r.t. 1 h.Wash plate 3×200 μL/well with TBST and add 100 μL/well Anti-rabbit IgGAb diluted 1:9000Incubate on rotator at r.t. for 1 h.Wash plate 3×200 μL/well with TBST and add 50 μL/well TMB substrate.Incubate r.t. till developed (blue, while maintaining dose response).Stop with 100 μL/well 1M HCL and read at 450 mm.Inhibition of tyrosine phosphorylation of HER2 in BT474 cells

Materials:

BT474 Cells grown in RPMI 1640 Gibco #11875-093, 10% FCSEssentially fatty acid free Bovine: Albumin SIGMA #A9205 30% solution96-well tissue culture treated plateEIA/RIA 96-well plates: Corning, Inc #9018HER2/ab-2: NeoMarkers, Inc. c-erbB-2/HER-2/neu Oncoprotein/Ab-2 (Clone9G6.10)

#MS-229-PABX

HER2/Ab-18: NeoMarkers, Inc. c-erbB-2/HER-2/neu biotin-tagged(Phospho-specific)

Ab-18 (Clone PN2A): #MS-1072-BO

Amersham Pharmacia Biotech Streptavidin-Horseradish PeroxidaseConjugate:

#RPN 1231

TMB Substrate: Sigma #T-8665 Wash Buffer: TBS/0.05% Tween Lysis Buffer:TBS 1% Triton X-100 1 mM EDTA

1 mM Sodium orthovanadate10 mM Beta glycerol phosphate

1 mM Sodium Fluoride

10 ug/ml Aprotinin1× Roche Complete EDTA-free protease inhibitor cocktail (1 tablet/2 mls1120)

Method: Day 1

Plate 30K BT474 cells/well (RPMI/10% FCS) in tissue culture treated96-well dish columns 2-12.Add 100 μL growth media to column one to act as signal to noise factor.

Incubate at 37° C.

Coat Antibody Plates: Dilute Her-2 Ab-2 in PBS to a final concentrationof 2 μg/ml.

Add 100 μL/well to 96-well EIA/RIA plates. Incubate on at 4 degrees C.on rotator.

Day 2

Block antibody plates: Wash plates 3×200 μL/well with TBST. Add 100μL/well TBST/3% BSA.Incubate 37° C. at least one hour.Make stock of basal media containing 0.1% BSA and sterile filter.Wash cell plates 2×100 μL/well with basal media and add 100 μL/wellbasal media/0.1% BSA.

Incubate 37° C. Incubate at 37° C. for 2 h.

Create master compound dilution plate at concentrations 3-fold desiredfinal concentrations.Initial concentration is in 0.1% BSA/Media. Subsequent dilutionsperformed in 0.1% BSA/Media containing 0.3% DMSO to match that found inthe initial drug concentration. Keep two columns without drug fordrug-free comparison. These columns should contain media/0.1% BSA/DMSOonly. Transfer 50 μL/well to cell plate containing 0.1% BSA/Media.

Incubate at 37° C. for 2 h.

Remove media and wash plate 2×150 μL/well with cold DPBS. Add 150uL/well cold Lysis Buffer containing protease inhibitors. Incubate onice 30 min rotating.Wash blocked antibody coated plate 3×200 μL/well with TBST. Transfer 100μL/well lysate to antibody coated plate. Incubate on rotator at 4° C.overnight.

Day 3

Wash plate 3×200 μL/well with TBST and add 100 μL/well Biotin-taggedphospho-Her-2 antibody diluted to 20 ng/mL in TBS/3% BSA. Incubate onrotator at r.t. for 1 h.Wash plate 3×200 uL/well with TBST and add 100 uL/wellStreptavidin-Horseradish Peroxidase Conjugate diluted to 100 ng/mL inTBS/3% BSA. Incubate on rotator at r.t. for 1 h.Wash plate 3×200 μL/well with TBST and add 50 μL/well TMB substrate.Incubate r.t. till developed (blue, while maintaining dose response).Stop with 100 μL/well 1M HCL and read at 450 nm.

In Vitro Tumor Cell Proliferation Assay

The utility of the compounds of the present invention can bedemonstrated, for example, by their activity in vitro in the in vitrotumor cell proliferation assay described below. The link betweenactivity in tumor cell proliferation assays in vitro and anti-tumoractivity in the clinical setting has been very well established in theart. For example, the therapeutic utility of taxol (Silvestrini et al.Stem Cells 1993, 11(6), 528-35), taxotere (Bissery et al. Anti CancerDrugs 1995, 6(3), 339), and topoisomerase inhibitors (Edelman et al.Cancer Chemother. Pharmacol. 1996, 37(5), 385-93) were demonstrated withthe use of in vitro tumor proliferation assays.

Many of the compounds and compositions described herein, exhibitanti-proliferative activity with IC₅₀ ≦50 μM in either of the followingspecified cell lines and are thus useful to prevent or treat thedisorders associated with hyper-proliferation. The following assay isone of the methods by which compound activity relating to treatment ofthe disorders identified herein can be determined.

In Vitro Tumor Cell Proliferation Assay

The tumor cell proliferation assay used to test the compounds of thepresent invention involves a readout called Cell Titer-Glow® LuminescentCell Viability Assay developed by Promega® (Cunningham, B A “A GrowingIssue: Cell Proliferation Assays, Modern kits ease quantification ofcell growth” The Scientist 2001, 15(13), 26, and Crouch, S P et al.,“The use of ATP bioluminescence as a measure of cell proliferation andcytotoxicity” Journal of Immunological Methods 1993, 160, 81-88), thatmeasures inhibition of cell proliferation. Generation of a luminescentsignal corresponds to the amount of ATP present, which is directlyproportional to the number of metabolically active (proliferating)cells.

A431 cells (human epidermoid carcinoma, ATCC #HTB-20) and BT474 (humanbreast carcinoma, ATCC #CRL-1555) were plated at a density of 2.5×10³cells/well in 96 well black-clear bottom tissue culture plates in RPMImedia with 10% Fetal Bovine Serum and incubated at 37° C. Twenty-four hlater, test compounds are added at a final concentration range from ashigh 100 μm to as low 64 μM depend on the activities of the testedcompounds in serial dilutions at a final DMSO concentration of 0.1%.Cells were incubated for 72 h at 37° C. in complete growth media afteraddition of the test compound. After 72 h of drug exposure, the plateswere equilibrated to room temperature for approximately 30 min. Then,using a Promega Cell Titer Glo Luminescent® assay kit, lysis buffercontaining 100 microliters of the enzyme luciferase and its substrate,luciferin mixture, was added to each well. The plates were mixed for 2min on orbital shaker to ensure cell lysis and incubated for 10 min atroom temperature to stabilize luminescence signal. The samples were readon VICTOR 2 using Luminescence protocol, and analyzed with Analyze 5software to generate IC₅₀ values. Representative compounds of thisinvention showed inhibition of tumor cell proliferation in this assay.

For determination of IC₅₀'s, a linear regression analysis can be used todetermine drug concentration which results in a 50% inhibition of cellproliferation using this assay format. The anti-proliferative activitiesof selective sets of compounds are listed below. In A431 cells, Examples1-7, 9-11, 14-18, and 20-21 have IC₅₀'s≦5 μM; whereas examples 8, 12,13, 19, and 22 have IC₅₀'s 50 μM. In BT474 cells, examples 1-7, 9-11,13-18, and 20-22 have IC₅₀'s≦5 μM; whereas examples 8, 12, and 19 haveIC₅₀'s≦50 μM.

C. OPERATIVE EXAMPLES RELATING TO PHARMACEUTICAL COMPOSITIONS

The compounds according to the invention can be converted intopharmaceutical preparations as follows:

Tablet: Composition:

100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50mg of maize starch (native), 10 mg of polyvinylpyrrolidone (PVP 25)(from BASF®, Ludwigshafen, Germany) and 2 mg of magnesium stearate.Tablet weight 212 mg, diameter 8 mm, curvature radius 12 mm.

Preparation:

The mixture of active component, lactose and starch is granulated with a5% solution (m/m) of the PVP in water. After drying, the granules aremixed with magnesium stearate for 5 min. This mixture is moulded using acustomary tablet press (tablet format, see above). The moulding forceapplied is typically 15 kN.

Orally Administrable Suspension: Composition:

1000 mg of the compound of Example 1, 1000 mg of ethanol (96%), 400 mgof Rhodigel (xanthan gum from FMC®, Pennsylvania, USA) and 99 g ofwater.A single dose of 100 mg of the compound according to the invention isprovided by 10 mL of oral suspension.

Preparation:

The Rhodigel is suspended in ethanol and the active component is addedto the suspension. The water is added with stirring. Stirring iscontinued for about 6 h until the swelling of the Rhodigel is complete.

1-17. (canceled)
 18. A method of treating a hyperproliferative disorderin a mammal, comprising administering to a mammal in need thereof aneffective amount of a compound according to formula (1)

wherein R¹ is selected from the group consisting of hydrogen, methyl,ethyl, and halo; R² is selected from the group consisting of hydrogen,methyl, ethyl, and halo; R³ is selected from the group consisting ofhydrogen, alkyl, halo, hydroxy, alkoxy, trifluoromethoxy, benzyloxy,halogenated benzyloxy, alkylated benzyloxy, pyridoxy, alkylatedpyridoxy, halogenated pyridoxy, pyridylmethoxy, halogenatedpyridylmethoxy, and N-morpholinyl, or R² and R³, together with thecarbon atoms to which they are attached, form an pyrazole ring, whereinsaid pyrazole ring can optionally be substituted with 0, 1 or 2substituents independently selected from the group consisting of alkyl,benzyl, halogenated benzyl, pyridylmethoxy, and halogenatedpyridylmethoxy; R⁴ is selected from the group consisting of hydrogen,alkyl, cyano, and halo; R⁵ is selected from the group consisting ofhydrogen, alkyl, and halo; R⁶ is selected from the group consisting ofhydrogen, and alkyl; R⁷ is selected from the group consisting ofhydrogen, and alkyl, or R⁷ is a heterocycle selected from the groupconsisting of pyrrolidinyl, morpholinyl, piperidinyl, and piperazinyl,or R⁷ is alkyl selected from the group consisting of methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl and t-butyl, wherein said alkyl issubstituted with 1, 2 or 3 independently selected substituents R⁷⁻¹,wherein R⁷⁻¹ is selected from the group consisting of halo, hydroxy,alkoxy, alkylsulfonyloxy, and amino, or R⁷⁻¹ is alkylamino, wherein saidalkylamino can optionally be substituted with 0, 1 or 2 substituentsindependently selected from the group consisting of hydroxy, alkoxy,amino, alkylamino, alkylsulfonyl, pyrrolidinyl, morpholinyl,piperidinyl, and piperazinyl, or R⁷⁻¹ is alkenylamino, wherein saidalkenylamino can optionally be substituted with 0, 1 or 2 substituentsindependently selected from the group consisting of oxo, hydroxy,alkoxy, amino, alkylamino, alkylsulfonyl, N-pyrrolidinyl, N-morpholinyl,N-piperidinyl, and N-piperazinyl, or R⁷⁻¹ is a heterocycle selected fromthe group consisting of pyrrolidinyl, imidazolidinyl, imidazolyl,pyrazolyl, morpholinyl, piperidinyl, piperazinyl, and thiomorpholinyl,wherein said heterocycle can optionally be substituted with 0, 1 or 2substituents independently selected from the group consisting of alkyl,halo, hydroxy, alkoxy, amino, alkylamino, hydroxyalkyl, alkoxyalkyl,carboxyl, alkoxycarbonyl, N-pyrrolidinyl, N-piperidinyl, N-piperazinyl,pyrazinyl, benzyl, and pyridylmethyl, or R⁷ is alkenyl selected from thegroup consisting of allyl, prop-1-enyl, 2-methyl-prop-1-enyl,but-1-enyl, but-2-enyl, but-3-enyl, pent-1-enyl, pent-2-enyl,pent-3-enyl, pent-4-enyl, wherein said alkenyl is substituted with 1, 2or 3 independently selected substituents R⁷⁻², wherein R⁷⁻² is oxo, orwherein R⁷⁻² is alkylamino, wherein said alkylamino can optionally besubstituted with 0, 1 or 2 substituents independently selected from thegroup consisting of oxo, hydroxy, alkoxy, amino, and alkylamino; or itssalt, solvate or solvate of the salt.
 19. The method of claim 18,wherein the hyperproliferative disorder is a cancer.